PURINETHOL
Clinical safety rating
cautionComprehensive clinical and safety monograph for PURINETHOL (PURINETHOL).
Comprehensive clinical and safety monograph for PURINETHOL (PURINETHOL).
Acute lymphoblastic leukemia (ALL) maintenance therapy (FDA-approved)Chronic myeloid leukemia (CML) (off-label)Inflammatory bowel disease (Crohn's disease, ulcerative colitis) (off-label)Autoimmune hepatitis (off-label)
Mercaptopurine is a purine antimetabolite that inhibits purine nucleotide synthesis and metabolism. It is converted intracellularly to 6-thioguanine nucleotides (6-TGNs), which incorporate into DNA and RNA, inhibiting their synthesis and function. It also inhibits de novo purine synthesis via feedback inhibition.
| Metabolism | Primarily metabolized by xanthine oxidase (XO) to 6-thiouric acid (inactive), and via thiopurine methyltransferase (TPMT) to 6-methylmercaptopurine (inactive). Activity of TPMT and NUDT15 affects toxicity. Allopurinol inhibits XO, leading to increased mercaptopurine levels. |
| Excretion | Primarily hepatic metabolism; renal excretion of metabolites accounts for approximately 50% of elimination. Biliary excretion contributes to a minor extent (<10%). |
| Half-life | The terminal elimination half-life of mercaptopurine is approximately 1.5 hours. However, the active metabolite 6-thioguanine nucleotides have a half-life of 5-7 days, correlating with pharmacological effects. |
| Protein binding | Approximately 19% bound to plasma proteins, primarily albumin. |
| Volume of Distribution | Volume of distribution is 0.9 L/kg, indicating distribution into total body water. |
| Bioavailability | Oral bioavailability is highly variable, ranging from 5% to 37% (mean approximately 16%), due to extensive first-pass metabolism. |
| Onset of Action | Oral: Therapeutic effects in leukemia may be observed within 2-3 weeks of continuous dosing. |
| Duration of Action | Oral: Duration of action is prolonged due to accumulation of active metabolites; therapeutic effects persist for several weeks after discontinuation. |
| Molecular Weight | 170.2 |
1.5-2.5 mg/kg orally once daily. Initial dose typically 50-75 mg/m²/day.
| Dosage form | TABLET |
| Renal impairment | GFR 50-80 mL/min: reduce dose by 25-50%. GFR 10-50 mL/min: reduce dose by 50-75%. GFR <10 mL/min: administer 50% of normal dose every 48 hours or consider alternative. |
| Liver impairment | Child-Pugh Class A: no adjustment. Child-Pugh Class B: reduce dose by 25-50%. Child-Pugh Class C: avoid use or reduce dose by 75%. |
| Pediatric use | Induction: 50-75 mg/m² orally once daily. Maintenance: 50-75 mg/m² orally once daily. Adjust based on tolerance and disease response. |
| Geriatric use | Start at lower end of dosing range (1.5 mg/kg/day). Monitor renal function and hematologic parameters closely. Reduce dose if significant renal impairment present. |
| 1st trimester | Mercaptopurine (Purinethol) is teratogenic in animals. Human data limited; potential risk of congenital malformations. Use only if maternal benefit outweighs fetal risk. |
| 2nd trimester | May be used if necessary; risks include fetal growth restriction and preterm birth. Monitor fetal growth. |
| 3rd trimester | May cause neonatal bone marrow suppression and immunosuppression. Consider withholding near term if possible. |
Clinical note
Comprehensive clinical and safety monograph for PURINETHOL (PURINETHOL).
| Placental transfer | Mercaptopurine crosses the placenta. Cord blood concentrations are approximately 60-80% of maternal serum concentrations. |
| Breastfeeding | Mercaptopurine is excreted into breast milk in low concentrations. No reports of adverse effects in infants. Caution is advised; monitor infant for signs of immunosuppression or bone marrow suppression. |
| Lactation Rating | L3 (Moderately Safe) |
| Teratogenic Risk | First trimester: Increased risk of congenital malformations including craniofacial defects, limb anomalies, and cardiovascular defects. Second and third trimesters: Risk of intrauterine growth restriction, preterm delivery, and fetal myelosuppression. Overall, considered teratogenic in humans; avoid use unless benefit outweighs risk. |
| Fetal Monitoring | Maternal: Complete blood count weekly, liver function tests, renal function. Fetal: Ultrasound for growth and anatomy, Doppler studies if IUGR suspected; monitor for signs of myelosuppression. |
| Fertility Effects | May impair fertility in both males and females. Males: Oligospermia, azoospermia. Females: Amenorrhea, ovarian failure. Effects may be reversible upon discontinuation. |
■ FDA Black Box Warning
Severe myelosuppression, especially with TPMT or NUDT15 deficiency. The drug is myelotoxic; fatal myelosuppression can occur. Monitor blood counts frequently.
| Serious Effects |
Hypersensitivity to mercaptopurine or any component of the formulationPrior resistance to mercaptopurine or thioguanineSevere hepatic impairment (Child-Pugh class C)
| Precautions | Myelosuppression: monitor CBCs regularly; reduce dose if severe., TPMT/NUDT15 deficiency: increased risk of severe myelosuppression; consider testing before therapy., Hepatotoxicity: monitor liver function tests; can cause hepatic veno-occlusive disease., Immunosuppression: increased risk of infections., Carcinogenicity: risk of secondary malignancies, especially with prolonged use., Pregnancy: Category D; may cause fetal harm. |
| Food/Dietary | Avoid grapefruit and grapefruit juice as they may increase drug levels. May decrease the effectiveness of warfarin; monitor INR if consuming vitamin K-rich foods. Alcohol consumption should be minimized due to potential hepatotoxicity. |
| Clinical Pearls | Purinethol (6-mercaptopurine) is a prodrug converted to active thioguanine nucleotides. Co-administration with allopurinol requires a 65-75% dose reduction of Purinethol due to inhibition of xanthine oxidase. TPMT genotyping or phenotyping is recommended prior to initiation to avoid severe myelosuppression. Monitor CBC and liver enzymes regularly. Avoid live vaccines during therapy. |
| Patient Advice | Take this medication exactly as prescribed, usually once daily. · Do not take with allopurinol unless specifically instructed by your doctor, as it may increase side effects. · Report any signs of infection (fever, sore throat), unusual bleeding/bruising, or jaundice immediately. · Avoid live vaccines (e.g., MMR, varicella) while on this medication. · Drink plenty of fluids to prevent kidney stones from uric acid accumulation. · If you miss a dose, do not double the next dose; take it as soon as remembered if within 12 hours of scheduled time. |
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